Indacaterol: a new long-acting bronchodilator effective in COPD patients

1) Department of Internal Medicine, Athena Villa dei Pini Clinic, Piedimonte Matese (CE);

2) Division of Internal Medicine, A.G.P. Piedimonte Matese (CE);

3) Physiopathology, Diseases and Respiratory Rehabilitation Unit, AORN Monaldi, Naples

COPD: Dimensions of the Problem

Chronic Obstructive Pulmonary Disease (COPD) is a chronic and only partially reversible condition of the airways, slowly progressive, caused by a "chronic inflammation of the airways and lung parenchyma. COPD is considered the fourth leading cause of death in Europe and the USA. (at least 65,000 deaths a year), recent studies have noted that mortality is on the rise worldwide.

The total incidence is 6-8%, it mainly affects adult males, but in recent years there has been a considerable increase in cases involving women.

The origin is a chronic inflammation that has lasted for years and affects the respiratory tract in the individual; this inflammation leads to a gradual loss of lung function. This dysfunction is not completely reversible, even if it is treated, and is mainly caused by smoking. Less common causes of COPD include passive smoking, environmental and occupational exposure to fine dust and chemicals.

Furthermore, a genetic predisposition to the disease (α1-antitrypsin deficiency) has been suspected for some time, which would explain the onset in some people unlike others with the same risk factors.

The disease at the end of the last century had an exponential growth, its presence in England alone in seven years increased by 25% in men and 69% in women.

Indacaterol and COPD

From now on there is a new ally to fight COPD, in fact the European agency (EMEA) has approved Indacaterol, a new drug developed by Novartis for the treatment of this disease.

Available by inhalation with once-a-day administration, Indacaterol has been approved in dosages of 150 and 300 mcg.
Previously known as QAB149, the drug was marketed under the brand name Onbrez Breezhaler®.

Indacaterol is the first beta-2 stimulant with 24 hour activity; before its introduction, an ultra long-acting anticholinergic, tiotropium, was already present, while currently the only long-acting beta-2 are salmeterol and formoterol which, however, have an average activity of 17 hours.
Indacaterol has shown a high selectivity towards beta-2 receptors, a rapid activity of action and a long duration of action, which exceeds 24 hours; in fact, it is characterized by a rapid onset of the effect - thanks to a short receptor interaction that eliminates both tachyphylaxis and tolerance problems - guaranteeing over time (52 weeks) an effect on the pre-dose FEV1 that is completely comparable to the initial effect.

It has no antagonistic effects towards drugs with beta-2 activity to be used as needed and has an excellent cardiovascular safety profile when compared with other beta-2 stimulants. Indacaterol induces muscle relaxation, consequently an increase in the diameter of the respiratory tract, typically reduced in COPD and asthma, while its anti-inflammatory action derives from the inhibition of the release of mediators by lung mast cells.

"Indacaterol represents the progenitor of a new class of beta2-adrenergic bronchodilators, (ULTRA-LABA), structurally distinct from formoterol, salmeterol and salbutamol which thanks to its chemical characteristics (Indacaterol Maleate, Amphiphilous Molecule and Micronized in dry powder for the" inhalation use) was the first bronchodilator with a duration of action of about 24 hours which allows for once daily administration.

Clinical Effectiveness

At the time of marketing, 4 clinical studies in COPD patients were available. The first compared the duration of action of indacaterol with tiotropium and was used to find the most appropriate dosage of the drug (dose finding study). was presented in Respiratory Medicine and compared different dosages of indacaterol in the first period, and then moved on to a treatment based on tiotropium. Concentrated dosages of indacaterol are between 150 and 300 mcg. At a distance of 24 hours after the administration of the drug, the various dosages tested showed a response in terms of bronchodilation, all in all quite homogeneous, and this prompted the company to choose the definitive posology (150 and 300 mcg). In comparison with tiotropium and placebo, indacaterol showed a better bronchodilation profile.

A second study was conducted on tolerability with different dosages up to doses of 600 mcg; even at these dosages (double the maximum recommended dose) no worrying side effects emerged in terms of glycaemia, heart rate and QT interval. So at dosages of 400 and 600 mcg the drug is well tolerated.

A third study again evaluated the safety and tolerability after single inhalations of increasing doses of indacaterol, up to 3000 mcg. The primary objective was safety: the study did not show anything significant and it should be remembered that these doses were 10 times higher than the dosage used in clinical practice.

The latest study compared indacaterol, salmeterol and formoterol in terms of FEV1 as well as inspiratory capacity. This study demonstrated the excellent efficacy of indacaterol also in terms of inspiratory capacity, meeting the needs outlined by a recent ERS document. / ATS related to the outcomes to be considered to evaluate the efficacy of treatments in COPD patients.
"Indacaterol behaves as a highly effective beta-2 adrenergic, with a faster onset of action than salmeterol and a significantly longer duration of action of both formoterol and salmeterol. The most common side effects highlighted following the" taking the drug, in clinical trials, are nasopharyngitis, cough, upper respiratory tract infections and headache. They were usually mild to medium in severity and became less frequent with continued therapy.
From the data in possession so far it can be deduced that:

Indacaterol possesses the characteristics of the ideal bronchodilator:
1. Selectivity
2. Bronchodilator effect in 24 hours
3. Rapid onset of action
4. Effective
5. Good safety profile
6. No antagonism towards rescue medication
7. Simple inhalation device requiring low inspiratory flows (PIF ≥ 50L / min)
The clinical development program of indacaterol has produced data indicating:
- Prolonged bronchodilation for 24 hours which allows once daily administration.
- FEV1 improvement in 24 hours
- Pre-dose FEV1 improvement.
- Clinically significant bronchodilation from the 1st dose
- Bronchodilation that persists after repeated dosing
- Rapid onset of bronchodilation (5 ")
- Effective reduction of symptoms
- Increased resistance to exercise
- Net improvement in the quality of life of the patients
- Excellent tolerability profile